Abstract

A wide range of diseases are caused by the generation of aberrant proteins that for one reason or another are not functionally
equivalent to the normal version. Here, we consider the basic cellular principles that govern the generation of aberrant proteins,
their normal metabolism and in the case of disease, their adverse effects on cellular function.

Key concepts

The organization of proteins inside cells is highly regulated at many levels.

Proteins that are not folded correctly or not trafficked to their intended destination are aberrant and have the potential
to cause cellular dysfunction.

Cellular organization of proteins. An illustration of the multiple layers of cellular organization that must be constantly
maintained by biosynthetic and trafficking pathways, and vigilantly monitored by quality control pathways. (a) Eukaryotic
cells contain numerous spatially distinct compartments whose environments differ considerably. For example, the endoplasmic reticulum (red) is an oxidizing
environment, the cytosol is a reducing environment, the cell surface (yellow) is exposed to the outside, endocytic and lysosomal
compartments (green) are acidic, and so on. (b, c) At the molecular level, each compartment is filled with its own unique
ensemble of proteins (and other macromolecules) whose precise composition and levels directly impact that compartment's function. For example, the cell surface contains channels and receptors whose identities
and amounts directly impact communication between the inside and outside of the cell, while the ER contains machinery for
protein translocation (the ‘translocon’). Molecular level organization is also determined by the assembly of many protein
constituents into appropriate functional complexes. The ER translocon is depicted as an assembly of a channel component (dark grey) associated with various additional factors
in the lumen and membrane. The receptor associates with cytosolic signalling molecules to function. (d) At the atomic level,
each protein acquires a precise three‐dimensional folded conformation that allows it to function. Shown is the structure of the channel‐forming component of the ER translocon (a heterotrimeric
protein called the Sec61 complex).

Figure 2.

Loss versus gain of function mechanisms. (a) Schematic depiction of the biosynthetic and degradation pathways of a cell surface
membrane protein (green) that is initially made at the ER, trafficked through the Golgi to the cell surface, and eventually
degraded in the lysosome. (b) In a purely loss of function mechanism, an aberrant version of this same protein (red) would
be efficiently recognized and degraded by the cell. Cellular dysfunction is due solely to the absence of the protein. (c)
In a gain of function mechanism, the aberrant protein would interact inappropriately with and influence the function of cellular
factors not typically encountered by the normal version. In this example, retention of the aberrant protein in the ER allows
it to interact with a resident protein (blue) whose altered function is the cause of cellular dysfunction.

Figure 3.

Multiplicity of toxic mechanisms by an aberrant protein. Dominant gain‐of‐function interactions by an aberrant protein (red)
can occur in many ways with different partners to cause cellular dysfunction. Most diseases are likely to involve multiple
interactions and multiple mechanisms, perhaps explaining their complexity. Some examples are: inappropriate interactions due
to altered conformation or residence in an incorrect location (1); failure to be degraded efficiently, generating aggregates
that sequester factors (2a) or inhibit organelle function (2b); interaction with and inhibition of QC or degradation machinery (3); generation of metabolites that are toxic (4); performing its function at an incorrect location
(5) and interaction with and inhibition of the normal version of the same protein (green) (6).